: Permissive Hypercapnia (PH), the tolerance of hypoventilation producing a state of elevated carbon dioxide (C02) and consequent acidosis, has been used in the care of patients with Acute Lung Injury (ALI). A multi-center trial of lung protective ventilation in mechanically ventilated patients with ALI showed a mortality benefit when small tidal volumes (6cc/kg) were compared to traditional tidal volumes. In this and previous studies, the benefits of lung-protective ventilation strategies were associated with significant hypercapnic acidosis (HA). However, there still is controversy whether, and to what degree, HA is beneficial in critically ill patients. Recent animal studies have shown that the use of inhaled CO2 significantly reduces lung injury when blood flow is re-established following a period of ischemia as measured by inflammatory mediators, lung edema, and gas exchange. There may be numerous, complicated, and inter-related effects of HA in disease states that clinically have been avoided due to the tendency to 'normalize" blood gas values in the treatment of severe lung injury. The first studies described in this application will attempt to confirm the beneficial effects of HA in two models of ALL, one applicable to the ischemia-reperfusion (IR) phenomenon that occurs with lung transplantation, pulmonary endarterectomy, and cardiopulmonary bypass; and the other to non-ischemic diffuse lung injury. The remaining studies are aimed at better understanding the mechanisms by which HA improves ventilation-perfusion (V/Q) matching in normal and disease states and describing the genetic response to HA in respiratory cells.